Project 2 Summary The incidence of cannabis use in the US population has been on the rise over the last decade and with legalization is likely to increase even further in coming years. This includes increases in the prevalence of use in adolescence both as a therapeutic and in social settings. Adolescent use presents special risks as brain networks are still developing and malleable. In this context, evidence that cannibis disturbs cognitive function and can impair learning and memory is a particular concern. Controlled studies with defined doses and outcome measures are clearly needed to understand these cognitive disturbances, and neurobiological processes underlying then. Studies in rodent have shown that exposure to cannabinoids (either ?9- tetrahydrocannabinol (THC), the psychoactive ingredient in cannabis, or a synthetic mimic) alters brain levels of components of the endocannabinoid (ECB) system and impairs specific forms of learning and memory. Less effort has been devoted to analysis of specific forms of synaptic plasticity thought to form the neurobiological substrate for memory or to projection-specific effects. Project 2 will evaluate both of these issues. Aim 1 will use electrophysiological (brain slice) techniques to determine if daily THC treatment of adolescent (ado) and young adult mice (both sexes) influences, and specifically impairs, synaptic transmission and activity-induced long-term potentiation (LTP) for three systems involved in memory encoding: (1) the lateral perforant path (LPP) afferents to hippocampus which we have found exhibits an ECB-dependent form of LTP, (2) Schaffer- commissural afferents to hippocampal field CA1 for which LTP is very well characterized and does not depend on ECB function, and (3) excitatory afferents to medial/prelimbic frontal cortex. Preliminary results indicate that THC effects are indeed projection specific: in male mice, daily ado-THC treatment eliminates the ECB- dependent form of LTP in the LPP. The same THC treatments impair, but do not eliminate non-ECB dependent field CA1-LTP but disturb processing of gamma-frequency afferent input to this region. Aim 1 studies will further determine if ado-THC effects on synaptic transmission persist into middle age, and are greater than effects of similar THC treatments applied to young adults. Aim 2 then will focus on hippocampal systems to test specific hypotheses as to the neurobiological processes underlying disturbances in synaptic plasticity and memory with ado-THC exposure: three sets of studies will test if changes in plasticity are associated with compartment-specific changes CB1R expression and CB1R signaling and if manipulation of ECB levels can offset impairments in synaptic function otherwise induced by ado-THC exposure. These studies have been designed to complement activities in other components of ICAL to provide an extensive vertical analysis of disturbances in substrates that underlie effects of THC on behavioral measures to be assessed in Project 3. Together this work will determine if mnemonic systems in the adolescent brain are particularly vulnerable to THC exposure and if levels of use in real world settings have enduring effects on higher cognitive function. !